Spectrum | Autism Research News

Blood lipid levels may be altered in some autistic people

Mon, 10 Aug 2020 15:00:00 GMT

Nearly 7 percent of autistic people in the United States have abnormal blood levels of fatty compounds called lipids, according to a study published today in Nature Medicine¹. The study’s approach, drawing on multiple datasets, could help researchers parse autism into subtypes, the researchers say.

Past studies have shown a link between this metabolic condition, called dyslipidemia, and autism in people with rare genetic conditions². But this is the first in-depth, multidimensional analysis to establish a robust association with autism more broadly, says Yuan Luo, study investigator and associate professor of preventive medicine at Northwestern University in Chicago, Illinois.

The study used a comprehensive approach integrating large datasets, including healthcare claims, electronic health records, familial gene sequences and an atlas of developmental gene-expression patterns.

Just as combining geographical data from various maps can help navigation tools create a more comprehensive view of the world, integrating datasets about various facets of autism can help us better understand the condition, says lead investigator Isaac Kohane, professor of biomedical informatics at Harvard University.

“Using one modality gives you only one perspective, whereas using multiple modalities gives you a holistic perspective,” he says.

Autism is a highly varied condition, with multiple genetic and environmental influences. Analyzing large and diverse datasets can help researchers parse the condition into smaller subgroups with shared phenotypes and devise bespoke treatments, Kohane says.

The new work may also help clinicians identify biological markers for screening autistic children early in development, rather than relying on behavioral traits.

“This is important because currently autism diagnosis is only based on symptoms. But when you actually see these symptoms, it’s already too late,” Luo says. “[These findings] could be of immediate clinical utility, and we plan to directly test those by future studies, including clinical trials.”

Layers of information:

First the team mapped out how genes work in concert during prenatal human brain development, a critical time window for autism. They used the BrainSpan online atlas to obtain data on the expression patterns of exons — the parts of genes that code for proteins — in 26 brain regions. They then narrowed in on clusters of exons that are expressed differently between boys and girls, given sex differences seen in autism.

Next, the researchers identified autism-related mutations found in the exons of autistic people. To do so, they searched a database of genetic sequences for 3,531 people from 50 families with two to five autistic children, looking for mutations shared by all autistic siblings within each family, as well as 1,704 families with autistic and unaffected sibling pairs, focusing on the mutations found only in the children with autism.

They then looked for overlaps between the exon clusters identified via the atlas and those with autism mutations, identifying 33 in common. Some contain the exons of genes involved in lipid protein regulation; mutations in them could lead to low levels of lipoproteins, cholesterol and triglycerides in the blood. The findings point to a possible association between autism and dyslipidemia, the researchers say.

To test this theory, the team analyzed medical records of 2.75 million people at Boston Children’s Hospital in Massachusetts, 25,514 of whom are children with autism. As a group, autistic children show significant alterations in blood lipid profiles compared with age-matched controls. For example, children with autism have higher triglyceride levels, regardless of age, medication, sex or metabolic conditions, such as obesity or diabetes.

The team examined healthcare claims for more than 34 million people across the United States, including 80,714 autistic people. They found that 6.6 percent of people with autism have dyslipidemia.

The study also found that parents with a history of dyslipidemia have up to a 16 percent greater odds of having autistic children — a result the researchers hope to investigate further in future studies, Luo says.

The findings jibe with previous research showing that dyslipidemia-associated genes are involved with several mechanisms key to neuronal function, such as controlled cell death.

However, it’s still unclear how lipids may affect the human brain, says Michael Snyder, professor of genetics at Stanford University in Palo Alto, California, who was not involved in the study. More research manipulating lipid levels — by either knocking out dyslipidemia-associated genes in mice or using medication — may offer a clearer understanding of this association.

In particular, researchers should try using lipid-lowering drugs, such as statins, in autistic people with dyslipidemia to determine whether the treatment improves their lipid levels and eases autism traits, Snyder says.

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Probe of DNA ‘repeats’ reveals new potential autism genes

Mon, 10 Aug 2020 11:00:00 GMT

Extra repeating bits of DNA may account for nearly 3 percent of the genetic architecture of autism, according to a new study¹. The work is the first to examine such genetic variants in autism on a large scale.

About half of the identified repeating sections occur in genes that have not been previously linked to autism, suggesting new lines of inquiry for geneticists.

“These genes are involved in autism, absolutely,” says study investigator Steve Scherer, professor of medicine at the University of Toronto in Canada. “Those [genes] will become diagnostic tests for the autism screening panel.”

The researchers looked at areas of the genome with tandem repeats — stretches of 2 to 20 nucleotides, which are the ‘building blocks’ of DNA, that are repeated two or more times in one spot. These repeats can expand when they are passed down from parents to children: If a nucleotide, or combination of them, is repeated 10 times in a parents’ DNA, it may be repeated hundreds of times in their child, for example. The more a repeat expands, the more likely it is that it will disrupt the gene’s function.

Some specific repeats are already associated with autism: About 5 percent of autistic people have fragile X syndrome, which is nearly always caused by the expansion of a particular repeat in the FMR1 gene. But less than a quarter of people with autism have a known genetic cause, even though twin studies suggest that autism is highly heritable².

Researchers have long suspected that expanded repeats may make up some of the condition’s missing heritability but did not have adequate methods or sample sizes to examine them in detail. The new work uses a novel statistical approach that scans whole genomes to parse differences in rare tandem repeat expansions between people with autism and their typical siblings.

“It kind of opens up a new dimension in terms of the class of genetic variants that we should be looking at, which I think is important,” says Santhosh Girirajan, associate professor of genomics at Pennsylvania State University in University Park, who was not involved in the work.

New autism genes:

The researchers analyzed the full genomes of more than 17,000 people, including 5,194 autistic people, 7,535 parents, 1,998 typical siblings and 2,504 unrelated controls. They focused on ‘outlier’ repeats that had more expansions in some individuals than in other members of the cohort, and further narrowed in on those that are found in less than 0.1 percent of controls. They identified 2,588 regions that are, on average, more expanded in autistic people than in their typical siblings.

Such rare repeats are expanded in 23.3 percent of autistic people compared with 20.7 percent of typical children, suggesting that repeats contribute up to 2.6 percent of the genetic influence on a person’s autism. The work was published in Nature in July.

The findings echo an unpublished study of about 1,600 families that was posted on a preprint server in March. That study found that autistic children had both more and longer repeat expansions than their typical siblings.

Scherer’s team also identified 57 areas of relevant genes, or loci, where tandem repeats occur more often in autistic children than in their typical siblings; 2.5 percent of autistic people in the study have repeat expansions in these loci. None would be picked up by the exome scans typically used to screen people for mutations in autism genes, Scherer says.

The repeats with rare expansions occur more often in genes involved in the nervous, muscular and cardiovascular systems, the study also found. By contrast, other genetic variants linked to autism, such as copy number variations, tend to occur solely in genes that affect neural function.

Some of the newly implicated genes, such as CACNB1, are already well-researched in the cardiac field and may help to explain the connection between autism and heart problems. If cardiac genes are implicated in autism, they may also open avenues for therapeutics, Scherer says.

The findings provide new targets both for researchers and for diagnostic tests as well, says Karun Singh, senior scientist at University Health Network in Toronto, Canada, who was not involved in the work.

“To find novel risk genes that are implicated in autism is very exciting,” he says. “It really provides new genes for the field.”

Further research:

Autistic people with rare expansions are more likely to have lower scores on tests of intelligence and social behavior than those who don’t, the study shows. And, within the identified genes, autistic girls have more rare expansions than autistic boys do.

Although the study found that repeats collectively contribute to autism, none are individually associated with the condition. That indicates that still larger datasets are needed, Girirajan says. It’s also possible that autism’s heritability stems from having a high overall burden of repeats rather than any specific ones, he says.

“In spite of having such a large number of genomes, it’s very interesting to see that we are still scratching the surface here,” Girirajan says. “If you’re looking for recurrence and reproducibility, you have to sample the whole universe before you find the same repeats over and over. And maybe still you won’t get it.”

The study also can’t explain the mechanisms by which tandem repeats contribute to autism, Singh says. Researchers should examine the newly identified genes in animal models and stem cells to better understand what role they are playing in the condition.

“They need to be investigated heavily by the field,” Singh says.

Scherer’s team continues to amass more whole genome sequences from autistic people and their families to study the repeats further using the statistical method they developed. He and others say the method is likely to be useful for studying the role of expanded repeats in other conditions — particularly ones for which large whole-genome sequence databases exist, such as schizophrenia and Alzheimer’s disease.

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Asthma common among children with autism, developmental disabilities

Fri, 07 Aug 2020 11:00:00 GMT

In the United States, children with autism or other developmental disabilities are at least twice as likely to have asthma as their typically developing peers are, according to a new study¹. And across all developmental disabilities, asthma is more prevalent among nonwhite children than white ones.

The results highlight the need for families, educators and caregivers to be able to recognize potential signs of asthma in developmentally disabled children, especially those who have trouble communicating, says lead researcher Sarah Messiah, professor of epidemiology at University of Texas School of Public Health in Dallas.

“It’s important to think about their holistic health and not just the disability,” Messiah says.

Previous studies of asthma and autism in young children have shown mixed results. Some have found an increased co-occurrence of the two conditions, as the new analysis does, but others show no correlation between them^2,3,4.

Some of this discrepancy may be explained by the fact that “both of those conditions are harder to assess during this early childhood period from age 0 to 5,” says Olivia Lindly, assistant professor of public health at Northern Arizona University in Flagstaff, who was not involved with the study.

Increased odds:

Messiah and her colleagues analyzed data from the 2016 and 2017 National Survey of Children’s Health, which collects demographic information from U.S. families, including parent education levels, income, race and ethnicity.

They focused on 71,811 families with children aged 17 or under that had reported on whether their child had been diagnosed with a developmental disability, such as autism, attention deficit hyperactivity disorder, seizures, hearing loss or a learning disability, and whether their child has or ever had asthma.

The researchers weighted the survey responses to be representative of the U.S. population and adjusted the results to ensure that certain measures, such as birth weight or family income, were not contributing to the differences in asthma prevalence.

Across all of the developmental disabilities evaluated, children with at least one disability were more likely to have asthma than children without a disability. Compared with their typical peers, children with hearing loss were three times as likely to have asthma, for example, and children with autism were nearly twice as likely to have the condition.

“It’s pretty consistent,” across developmental disabilities, says Lisa Croen, senior research scientist at the Kaiser Permanente Division of Research in Oakland, California, who was not involved in the study.

The team also found racial and ethnic differences. Nearly 1 in 5 ethnic minority children with at least one developmental disability were also diagnosed with asthma at some point in their lives, compared with 1 in 8 non-Hispanic white children with at least one developmental disability.

The results were published in June in JAMA Network Open.

Autism associations:

The study did not examine how racial disparities break down for children from different ethnic backgrounds. But the finding that children of color are more likely to have asthma than white children is consistent with previous research⁵.

“There are huge economic disparities,” between white and nonwhite children in this county, Croen says. “And those economic disparities across racial and ethnic groups can lead to huge health disparities, asthma being one of them.”

Messiah and her colleagues also did not compare asthma prevalence across age groups in their paper, but unpublished data they have collected suggest that the link between asthma and autism is weakest in children under age 5. For children with autism, it seems that “the odds of having current asthma increase with age,” Messiah told Spectrum in an email.

Another limitation of the study is that because it is cross-sectional, its findings are only associations.

“Is asthma leading to higher rates of developmental disability or is developmental disability somehow leading to higher rates of asthma? We really can’t know from this kind of study,” Lindly says.

The researchers are looking into potential causal pathways between these conditions for their next steps.

One theory is that asthma and developmental disabilities have some common genetic underpinning, Croen says. Looking at genetic similarities between these conditions may provide clues as to how the conditions are connected.

Or it may be that asthma and developmental disabilities are influenced by a mother’s immune system. Some studies have found that mothers with asthma or immune disorders are more likely to have a child with autism, for instance.

For now, one of the most important takeaways is that parents of children with developmental disabilities remain their child’s best advocate, Messiah says.

“Any symptoms of wheezing, difficulty breathing, then it’s time to look up the pediatrician and get a screening.”

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Autism prevalence estimates for China, Greece align with global patterns

Thu, 06 Aug 2020 11:00:00 GMT

About 0.7 percent of children in China aged 6 to 12 have autism, suggests the largest study of the country’s autism prevalence to date¹. And in Greece, 1.15 percent of 10- and 11-year-olds have the condition, according to the first estimate for that country².

Both figures fall within the range of autism prevalence estimates reported for children in other nations. The studies also show that autism is about four times as common in boys as it is in girls in both countries, a ratio in line with studies of children in the United States and elsewhere.

A 2019 study of 45,036 children in three Chinese cities came up with a slightly higher estimate of about 1 percent. But the new work includes almost three times as many children, from eight cities, and may better represent China’s population, the researchers say. It also provides the first data on the prevalence of co-occurring conditions, such as attention deficit hyperactivity disorder, phobia or obsessive-compulsive disorder.

“It’s a very strong starting point, and it’s a step up for China compared to what was there before,” says Eric Fombonne, professor of psychiatry at Oregon Health and Science University, who helped design the study, a collaboration among researchers across five provinces and three municipalities — groups that often compete for government research funding. “These epidemiological studies are behemoths, very difficult to do.”

Still, the new studies may underestimate the actual number of children with autism in China and Greece.

Autism prevalence research in both countries is in early stages compared with prevalence research in other countries, says Mayada Elsabbagh, assistant professor of neurology and neurosurgery at McGill University in Montreal, Canada, who was not involved in either study. Instead of true prevalence, the new estimates in China and Greece likely reflect levels of community awareness, the quality of services and the availability of diagnostic tools, she says.

Identifying children:

Fombonne and his colleagues used government records to identify 125,806 eligible children ages 6 to 12 living in eight Chinese cities, chosen as a representative sample of the country. To screen the children for autism, the team distributed a questionnaire they had developed, called the Modified Chinese Autism Spectrum Rating Scale (MC-ASRS), to parents and teachers.

The MC-ASRS screen flagged 37,500 children. After group interviews with the children, the team offered diagnostic evaluations to 1,135 of them; about 20 percent of the children’s families declined. The team also evaluated children attending special education schools, who they assumed were more likely to be autistic.

Of the 1,079 of children evaluated for autism, 363 met criteria for the condition. Forty-three percent of the children had not been previously diagnosed, and more than 90 percent of these children attended mainstream schools. By assuming that the prevalence numbers for children from nonresponsive families would be roughly the same as those for the rest of the participants, the researchers estimated an overall prevalence of 1 in 143.

This figure falls on the lower end of the range reported for other countries, suggesting that more children remain to be identified in the region, Elsabbagh says. “It’s nevertheless a very useful tool to get kind of a screenshot of the current situation of autism in China, and certainly a useful estimate in terms of informing policy and services.”

The study shows that 69 percent of autistic children in China have at least one co-occurring neuropsychiatric condition, the most common of which is attention deficit hyperactivity disorder, identified in 43 percent of them. Medical records for about 30 percent of the children showed that the most common co-occurring physical conditions are gastrointestinal problems, sleep disorders, allergies and seizure disorders.

The inclusion of data on co-occurring conditions is a welcome contribution of the study, Elsabbagh says. “Here the picture is somewhat consistent with some of the reports we get from other countries.”

Early steps:

The Greek study, the first large-scale autism prevalence study in that country, relied on education records to determine the autism status of 182,879 children. It shows a prevalence of about 1 in 87.

The approach appears to achieve good coverage of the country’s 10- and 11-year-olds, yielding results that line up closely with other autism prevalence estimates, Elsabbagh says. But, she adds, “one could argue the use of data that doesn’t involve doing direct assessments is problematic.”

The numbers would likely be more reliable if researchers had done follow-up clinical interviews with children, Fombonne says. Unlike the Chinese study, the Greek study does not include data on co-occurring conditions, but the researchers present a fair and accurate picture of the limitations of their findings, he says.

Spectrum could not reach the researchers behind the Greek study for comment.

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New ‘synaptome’ maps neuronal connections in mouse brain across lifespan

Wed, 05 Aug 2020 11:00:00 GMT

A new atlas lays bare how neuronal connections, or synapses, change from birth to old age in mice¹. The ‘synaptome’ may help researchers investigate how mutations linked to autism affect these connections at different stages of life.

Synapses are the junctions where information is transferred between cells, and they are integral to functions such as learning, behavior and movement. Autism is linked to several mutations that alter synaptic proteins.

In 2018, researchers created the first synaptome of the mouse brain, mapping billions of synapses and sorting them into types based on their size, shape and composition². The map revealed that synapse subtypes have distinct distributions in the brain, suggesting they have specific functions. This synaptome mapped the mouse brain only at one point in time, however.

In the new work, the team charted five billion synapses in mice at 10 different ages, revealing how synapses change in number, structure and molecular makeup throughout life.

“It’s the first time anybody’s ever done that in any species,” says Seth Grant, professor of molecular neuroscience at the University of Edinburgh in Scotland, who led the research.

To create the atlas, the team engineered mice to express fluorescent markers of different colors on two proteins — PSD95 and SAP102 — that frequently line the signal-receiving end of excitatory synapses, which make up the preponderance of synapses in the brain. Mutations in these proteins have been linked to autism, schizophrenia and intellectual disability.

The researchers then took brain images of mice across the animals’ lifespan, from 1 day to 18 months old, with clusters of the two proteins revealing the location of the synapses. They used machine learning to automatically sort synapses into three types based on the proteins present — PSD95, SAP102 or both — and 37 subtypes based on their shape and size.

Age adjustments:

The synaptome changes throughout life, the researchers reported in July in Science. These changes can be split into three phases that correspond to the mouse equivalent of childhood and adolescence, early adulthood and late adulthood in people.

In the first phase, from birth to 1 month of age, synapse density increases rapidly. The number of synapses then levels off in the second phase and, after 6 months, begins to decline as the mouse enters old age.

The types of synapses in the brain also diversify quickly in the first phase. They continue to change throughout life, with particular synapse types and subtypes peaking at different ages in distinct brain regions.

In fact, brain regions develop different synapse compositions during the first three months of life. This may explain why brain areas develop specialized functions, Grant says.

In old age, however, synapses across brain regions begin to resemble one another, which may underlie declines in cognitive function and changes in behavior that are typical of aging.

The lifespan synaptome, which can be explored online, could help researchers gain a better understanding of why mutations linked to autism or other conditions affect synapses in specific brain regions at certain ages, the researchers say. The team is currently mapping the synaptome of mice carrying mutations to study how genetic alterations affect synapses throughout life.

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Beyond the bench: A conversation with Matthew Lerner

Tue, 04 Aug 2020 11:00:00 GMT

Under normal circumstances, Matthew Lerner’s day is full of meetings with graduate students, postdoctoral researchers, clinicians and research participants. His work focuses on how autistic people navigate relationships and what factors can facilitate or impede meaningful connections.

Since the pandemic began, his days have taken on a new dimension: They’re still full of meetings, but now Lerner and his team are part of a massive global experiment on maintaining social connection while working remotely.

Some of their efforts, such as in-person mentorship programs for autistic teenagers, just aren’t possible with social distancing — and likely won’t be in the near future. But Lerner is optimistic that the autistic people who work with his team can teach researchers some lessons about forging social connection in a world that isn’t set up for it.

Spectrum: What is the big question that drives your research?

Matthew Lerner: For most people, being able to connect to others, make friends and develop meaningful relationships happens fairly effortlessly. But for some people, especially those on the spectrum, it can be really hard. So the thing that we want to understand here is, what are the factors that make that happen, that can either facilitate or get in the way? And then how do we use those insights to improve interventions and approaches that are both effective and respectful of the preferences of the population? And then finally, how do we get those things out into the world?

S: Whose work do you admire? And whom would you love to work with one day?

ML: Oh man, there are so many people whose work I admire in this field. In particular, Connie Kasari has long been a hero of mine. I feel like she’s always been about 10 steps ahead of everybody else who’s doing any kind of intervention work, and she was incorporating insights of autistic individuals into research on intervention long before most people thought of doing that. I’ve long hoped to work with her.

S: How much sleep do you usually get?

ML: Not enough. I would say if I get six hours, it’s a good day.

S: What does your day look like these days, during the pandemic?

ML: My wife actually works in the pediatric emergency room, so she’s busy. And so I’m basically trying to figure out how to get my kids some structure for the day and almost every day doing some combination of schooling and play, hopefully getting a little bit of fresh air every once in a while. And, of course, I have meetings every day with my students, postdocs, staff and colleagues so we can keep the lab going now; most of my day involves balancing this with childcare and cooking meals. Also, I have played saxophone since I was a child, and used to play in many different types of bands (jazz, ska, funk, experimental, rock, klezmer); while I don’t really have time to be in any bands right now, I hope to do so again one day, and for now I enjoy getting to play solo a bit whenever I can.

As somebody who studies social connection and social interaction, I find this sort of massive worldwide experiment in social distancing to be worrying and also interesting. Worrying just because we are a eusocial species. We do still need connection. So how we’re going to deal with being isolated from one another for an indeterminate amount of time is going to be hard. We’re already seeing all of these different ways people are desperately trying to innovate these connections, figuring out what means of connection works for them.

One thing it’s definitely doing is causing us to be more explicit and intentional about our social interactions. On the one hand, it may cause us to be more cautious. It may cause us to pause and maybe even be more empathic, to really think carefully about “Who am I talking to?” and “What are their needs?” and “How can I adjust; how can I calibrate to them?”

In our lab, we try really hard to integrate insights from autistic individuals. I’ve talked to a few colleagues of mine who are on the spectrum about how things are going during the pandemic. A few people have said, “I’ve been waiting for this for a long time, and I feel like I have a lot of insights to share with the neurotypical world about how to manage a more socially distant, intentional existence.” So, we’re trying to learn from them.

One thing we’ve learned from many of our studies is that because of some of the factors that can impact the ability to have fluid social-interactive behavior, autistic individuals are more practiced at being intentional. This is something that we really might be able to learn from our autistic friends and colleagues: how to better manage in a world that looks like this.

Double duty: The bulk of Lerner’s writing happens during his ‘second shift,’ which begins after he and his wife put their kids to bed.

S: How do you stay productive?

ML: I try to find time where I can, and I try to preserve time as well. The notion of protecting one’s time is really so invaluable and relevant here. There’s a great book by the psychologist Paul Silvia called “How to Write a Lot.” It’s a slim little volume, and it’s one of the best guidebooks for productive writing. Also, Andres De Los Reyes of the University of Maryland has a new book called “The Early Career Researcher’s Toolbox,” which gives guidance on productivity and finding your voice in research and how you’re to do all this — the mechanics of all of it.

Both Paul and Andy have similar advice, which is finding some time — even if it’s 10 or 20 or 30 minutes — on a regular basis to be your writing time and making sure that it is unencumbered. And also realizing that writing doesn’t necessarily mean literally putting pen to paper or fingers to keyboard. Writing can mean just taking time to think about your science and the questions you’re asking, or taking time to read related articles or formulate your thoughts. So when you approach it that way, when you’re creating those little 10-minute windows, you can forgive yourself if at the end of it if you haven’t written 500 words.

I usually write at home at night, during my ‘second shift’ (i.e., after my kids are in bed). Sometimes I’ll do writing with my graduate students when we meet. Or we’ll sort of sit down and be like, “Alright, let’s pick apart this arc. Let’s figure out how we’re going to make this case as clearly as we can.”

And then in terms of background stuff, I usually toggle between, like, a Pandora or some kind of background music station without words. Or sometimes, and Andy De Los Reyes actually talks about this in his book, there are some movies or TV shows that I just like a lot and know so well that I can have them on in the background and it’s almost like they don’t have words.

S: What do you put on the TV?

ML: “Star Trek: The Next Generation” is my current one. “30 Rock” and “How I Met Your Mother” are great ones. Many of the Marvel movies are good ones for me, as well as Star Wars movies.

I used to beat myself up about this because I felt like I have all this stuff to get done, but I need to decompress. Just listening to ambient music is not enough to really decompress, but there’s just not enough time, and then I realized, hey there are some things that I enjoy just fine, and yes they have words but I can still get that benefit, that relaxation, and also that dopamine burst of something I really enjoy, and pair it with my writing.

S: What are you reading right now?

ML: I read The Atlantic magazine a lot, pretty much everything that comes out. I started reading “The Magic Treehouse” series with my son. It’s sort of like the one-generation-younger Harry Potter, similar stories for slightly younger kids. It brings me so much joy to read with him — we look forward to it every night.

As for academic journals, mostly I’m reading what my grad students bring me, or the articles I review as a peer reviewer or editorial board member.

S: Are you active on social media?

ML: I am on Facebook and MeWe, but I’m not on Twitter. I’m trying to get more active on MeWe because I’m trying to figure out if it’s possible to get off of Facebook. MeWe is one of these new platforms that’s much more transparent about what they do with your data. I’m trying hard to believe that Twitter doesn’t exist, but I don’t know how long it’s going to last. Right now, paradoxically, social media is the main way that many of us are connecting with one another.

S: What do you eat or drink while you’re working?

ML: Coffee. A lot of coffee.

S: How many unread emails are in your inbox right now?

ML: 70.

S: That’s not too bad.

ML: —70 threads.

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Studies unravel diversity of traits tied to chromosome 16 mutations

Mon, 03 Aug 2020 11:00:00 GMT

Mutations to the chromosomal region 16p11.2 affect people in different ways, often leading to some combination of autism, intellectual disability and language difficulties. Two new studies help to account for this diversity of traits^1,2.

Up to 25 percent of people with a duplication or deletion of DNA, or copy number variation (CNV), in 16p11.2 have autism; the rest often have at least one autism trait, according to previous research. People with 16p11.2 CNVs also have varying levels of cognitive and language abilities. And as with other genetic influences on autism, 16p11.2 CNVs seem to affect boys more often, or at least more severely, than girls.

“We’re looking across different parts of the phenotype and trying to understand how all of these pieces connect together,” says Caitlin Hudac, assistant professor of psychology at the University of Alabama in Tuscaloosa.

One of the new studies, led by Hudac, explored how various traits relate to additional genetic and environmental factors in 96 people with 16p11.2 deletions and 77 with duplications.

The researchers tallied each participant’s experiences of perinatal and prenatal events associated with autism, such as having a low birth weight or a mother who had preeclampsia.

They also sequenced the participants’ DNA to identify other mutations that could have contributed to the traits, which they assessed using standardized tests. They then developed a statistical model that, based on five factors — number of prenatal events, number of perinatal events, other CNVs, other gene mutations, and sex — accounted for 9 to 20 percent of the variability in individual traits.

For example, deletion carriers who had experienced the most perinatal events tended to have a low verbal intelligence quotient (IQ) and poor adaptive behavior, or the ability to carry out daily tasks such as eating or getting dressed, the researchers found. And duplication and deletion carriers who had experienced a higher number of perinatal events or had additional CNVs tended to have a low nonverbal IQ.

The researchers also saw a ‘female protective effect’: Compared with their male counterparts, female duplication carriers were less likely to have difficulties with social interaction, and female deletion carriers were less likely to have restricted and repetitive behaviors.

The work was published in June in Autism Research.

Language specifics:

The results are in line with the idea that multiple factors work together to contribute to variation in autism traits, says Santhosh Girirajan, associate professor of genomics at Pennsylvania State University in University Park, who was not involved in either study. The 16p11.2 CNVs on their own “are not deterministic,” he says.

The second study, conducted by a different team, similarly shows how variable the effects of 16p11.2 deletions and duplications are by focusing on a single outcome: language impairment.

“Many past studies have highlighted language impairments mostly in deletion carriers, mainly by giving language testing in highly structured settings,” says lead researcher So Hyun “Sophy” Kim, assistant professor of psychology in clinical psychology at Weill Cornell Medical College in New York City.

Kim and her colleagues used multiple complementary testing methods, including one that allowed them to evaluate language abilities in a naturalistic setting. They tested 110 children and young adults with a 16p11.2 deletion and 58 with a duplication.

Deletion and duplication carriers both “seemed to show difficulties using their language in a social way,” Kim says. In particular, the children had the most trouble with pragmatic language, or “being able to have back-and-forth conversation with someone, sharing interests and offering information about” their own experiences.

The difficulties existed even in children with no autism diagnosis or cognitive deficit, suggesting that this language impairment is characteristic of the CNVs. The results were published in June in the American Journal of Medical Genetics.

Identifying needs:

Learning more about the diversity of traits across people with 16p11.2 CNVs could help “identify the different needs and the different abilities of people with these genetic variants,” says Nicola Grissom, assistant professor of psychology at the University of Minnesota in Minneapolis, who was not involved in either study.

Researchers from both studies suggest that the most effective way to influence positive outcomes for children with 16p11.2 CNVs is early identification and intervention.

For language impairments, that means starting therapy before age 5, when an explosion of language development is thought to occur, Kim says. Comprehensive language assessments can help ensure that happens.

“The ultimate goal,” Hudac says, “is to be able to understand how everything works together in order to develop successful treatments.” Her team is incorporating additional factors into their statistical model, such as the genetic and environmental backgrounds of a person’s parents, in an attempt to further explain the variability in 16p11.2 CNV-associated traits.

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